Novel antifertility agents

ABSTRACT

Derivatives of 2-aroyl-3-phenylindenes, 3-aroyl-4-phenyl-1,2-dihydronaphthalenes, and 1-phenyl-2-aroyl-naphthalenes are useful as antifertility agents.

This is a division, of application Ser. No. 625,992, filed Oct. 28,1975, now U.S. Pat. No. 4,017,546.

BACKGROUND OF THE INVENTION

This invention relates to novel compounds. More particularly, thisinvention relates to novel compounds which possess valuable utility asantifertility agents and thus are useful in the control of animalpopulations. In another aspect, this invention relates to a novel methodof inhibiting pregnancy and to a novel method of controlling animalpopulations.

The prior art has recognized various classes of compounds, each havingthe general formula ##STR1## IN WHICH Ar is an aryl moiety and Y is anyof various groups, such as --CH₂ --, --CH₂ --CH₂ --, --S--, --NH, --OCH₂--, --O--, --CH₂ S--, and --SCH₂ --. Many compounds within these generalclasses are described as having antifertility activity.

Lednicer et al., J. Med. Chem., 8, (1965), pp. 52-57, discloses2,3-diphenylindenes and derivatives thereof as antifertility agents.

Lednicer et al., J. Med. Chem., 9, (1966), pp. 172-175; Lednicer et al.,J. Med. Chem., 10 (1967), pp. 78-84; and Bencze et al., J. Med. Chem., 8(1965), pp. 213-214, each disclose various1,2-diaryl-3,4-dihydronaphthalenes as active antifertility agents. Inaddition, U.S. Pat. Nos. 3,274,213; 3,313,853; 3,396,169; and 3,567,737disclose various 1,2-diphenyl-3,4-dihydronaphthalenes as usefulantifertility agents.

Other United States Patents disclose both1,2-diphenyl-3,4-dihydronaphthalenes and 2,3-diphenylidenes as activeagents. These include U.S. Pat. Nos. 3,293,263; 3,320,271; 3,483,293;3,519,675; 3,804,851; and 3,862,232.

In addition, Crenshaw et al., J. Med. Chem. 14, (1971), pp. 1185-1190,disclose among others, various 2,3-diarylbenzothiophenes as exhibitingantifertility activity. Certain of these compounds are claimed in U.S.Pat. No. 3,413,305. Crenshaw et al. additionally disclose othercompounds which participate in the general classes describedhereinabove. 2,3-Diarylbenzofurans corresponding generally to the abovebenzothiophenes are disclosed and claimed in U.S. Pat. No. 3,394,125.

A need still exists to provide additional compounds useful asantifertility agents and, in particular, nonsteroidal antifertilityagents. The novel compounds of this invention fill such a need. They are2-aroyl-3-phenylindenes, 3-aroyl-4-phenyl-1,2-dihydronaphthalenes, and1-phenyl-2-aroylnaphthalenes, and, structurally, they differsignificantly from those described in the aforementioned prior art. Itis an object therefore of this invention to provide novel nonsteroidalcompounds having antifertility activity.

SUMMARY OF THE INVENTION

These as well as other objects are achieved by this invention whichcomprises a class of compounds having the formula ##STR2## in which X is--CH₂ --, --CH₂ --CH₂ -- or --CH═CH--; R and R₁ independently arehydrogen, hydroxyl, C₁ - to C₅ -alkoxy, or C₅ - to C₆ -cycloalkoxy;subject to the limitation that at least one of R and R₁ is hydrogen; R₂is hydrogen, chloro, bromo, hydroxyl, C₁ - to C₅ -alkoxy, or C₅ - to C₆-cycloalkoxy; subject to limitation that at least one of R, R₁, or R₂ isother than hydrogen; and R₃ is hydrogen or ##STR3## in which R₄ and R₅independently are C₁ -C₄ alkyl, or R₄ and R₅ taken together with thenitrogen to which they are bonded constitute a heterocyclic ringselected from the group consisting of pyrrolidino, piperidino,hexamethyleneimino, or morpholino; and pharmaceutically acceptablenon-toxic acid addition salts of those compounds in which R₃ is ##STR4##

As indicated above, this invention also includes the pharmaceuticallyacceptable non-toxic salts of those of the above compounds in which R₃is ##STR5## The pharmaceutically acceptable non-toxic salts include theorganic and inorganic acid addition salts, for example, those preparedfrom acids such as hydrochloric, sulfuric, sulfonic, tartaric, fumaric,hydrobromic, glycolic, citric, maleic, phosphoric, succinic, acetic,nitric, and the like. Preferably, the acid addition salts are thoseprepared from citric acid. Such salts are prepared by conventionalmethods.

The term "C₁ -C₄ alkyl" as used herein contemplates both straight andbranched chain groups such as methyl, ethyl, n-propyl, isopropyl,n-butyl, t-butyl, isobutyl, and sec-butyl.

The term "C₁ -C₅ alkoxy" as used herein contemplates both straight andbranched chain alkyl radicals and therefore defines groups such as, forexample, methoxy, ethoxy, n-propoxy, isopropoxy, n-butyloxy,isobutyloxy, t-butyloxy, sec-butyloxy, n-amyloxy, isoamyloxy, t-amyloxy,sec-amyloxy, and the like.

The term "C₅ -C₆ cycloalkoxy" as used herein contemplates cyclopentyloxyand cyclohexyloxy.

A preferred subclass of the compounds of this invention are thedihydronaphthalenes, that is, in the above formula, those compounds inwhich X is --CH₂ -Ch₂ --.

Of the defined dihydronaphthalenes, several preferred subclasses exist.One such subclass is comprised of 7-hydroxy-1,2-dihydronaphthalenes,that is, those compounds in which X is --CH₂ -CH₂ -- and R₁ is hydroxyl.

Another such subclass includes the3-(4-hydroxybenzoyl)-1,2-dihydronaphthalenes, that is, those compoundsin which X is --CH₂ -CH₂ -- and R₂ is a hydroxyl group and is located inthe position para to the carbonyl function.

A further preferred subclass includes the 4-[4-(2-disubstitutedaminoethoxy)phenyl]-1,2-dihydronaphthalenes, that is, those compounds inwhich X is --CH₂ -Ch₂ -- and R₃ is ##STR6## When R₃ is so defined, it isfurther preferred that both R₄ and R₅ are methyl, both R₄ and R₅ areethyl, or R₄ and R₅ taken together with the nitrogen to which they arebonded constitute a pyrrolidino ring.

The compounds of this invention are prepared by the following sequences,the dihydronaphthalene structures being precursors to the naphthalenecompounds.

A. Preparation of compounds in which X is --CH₂ --

These compounds are prepared from β-phenylpropionic acids of the formula##STR7## in which R_(1a) is in the meta or para position and ishydrogen, C₁ - to C₅ - to C₆ -cycloalkoxy, phenacyloxy, orp-halophenacyloxy. The acid is ring closed by treatment withpolyphosphoric acid to produce the corresponding oxoindane ##STR8## Theoxoindane (II) is treated in the presence of an alkali metal amide withan ester of the formula ##STR9## in which R_(2a) is hydrogen, chloro,bromo, C₁ - to C₅ -alkoxy, C₅ - to C₆ -cycloalkoxy, phenacyloxy, orp-halophenacyloxy, to produce ##STR10##

The compound III then is converted to a compound of this invention byreaction with phenylmagnesium bromide or p-methoxyphenylmagnesiumbromide to produce ##STR11## in which R_(3a) is hydrogen or methoxyl.

When it is desired that any of R_(1a), R_(2a), and R_(3a) be hydroxy,such is available from the corresponding alkoxy compound by treatment ofthe latter with pyridine hydrochloride at a temperature of from about200° C. to about 250° C.

Selective cleavage of the methoxy groups can be accomplished by the useof reagents which preferentially attack a methoxy group located at aparticular position of the molecule. Thus, if it is desired to cleave amethoxy group at R_(2a) while retaining intact a methoxy a R_(1a) and/orR_(3a), this can be accomplished using sodium thioethoxide. The compoundis reacted with sodium thioethoxide in an inert solvent at a moderatelyelevated temperature of from about 50° C. to about 80° C. for a periodsufficient to accomplish the desired reaction. The ongoing of thereaction can be monitored by periodic thin-layer chromatographicanalysis (TLC) of the reaction mixture. The reaction is complete whenlittle or no starting material remains.

When the methoxy group to be cleaved is located at R_(1a) and/or R_(3a),this can be accomplished without affecting a methoxy at R_(2a) byreacting the compound with boron tribromide. The reaction is carried outin an inert solvent, preferably methylene chloride. In the event that amethoxy group is present at both R_(1a) and R_(3a), the product whichresults will be dependent upon both the time and temperature of thereaction. When the reaction is carried out for an extended period, forexample, 20-36 hours at room temperature, both methoxy groups will becleaved to the dihydroxy compound. This can be modified by shorteningthe reaction time, in which case a mixture of products will resultrepresenting cleavage either of the methoxy at R_(1a) or the methoxy atR_(3a). In this event the desired product can be separated from themixture by employing standard techniques, such as chromatographicseparation.

Alternatively, R_(1a) and/or R_(2a) can be phenacyloxy orp-halophenacyloxy, such as p-chlorophenacyloxy or p-bromophenacyloxy.Any of these phenacyl groups are suitable as protecting groups, beingreadily cleaved upon treatment with zinc and acetic acid at about 60° C.for approximately one hour to form the corresponding hydroxy compound.The particular sequence of synthetic steps designed to produce acompound having substituents of particular definition and location issuch as one of ordinary skill in the art will well recognize.

Compounds in which R_(3a) is ##STR12## are available from thecorresponding compound in which R₃ is hydroxy by treatment thereof inthe presence of sodium hydride with a compound of the formula ##STR13##in which Z is halo, particularly bromo or chloro.

B. Preparation of compounds in which X is --CH₂ -CH₂ --

These compounds are prepared by a method analogous to that desired abovefor preparation of the indene compounds, the principal difference beingthe use of a tetralone of the formula ##STR14## in which R_(1b) is inthe 6- or 7-position and is hydrogen, C₁ - to C₅ - alkoxy, C₅ - to C₆-cycloalkoxy, phenacyloxy, or p-halophenacyloxy.

C. Preparation of compounds in which X is --CH═CH--

These compounds are readily prepared from the aforementioned compoundsin which X is --CH₂ -CH₂ --. Selective dehydrogenation of thedihydronaphthalene structure to produce specifically the correspondingnaphthalene can be accomplished by treatment of the former with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) at a temperature of fromabout 50° C. to about 100° C.

Again, by means of the aforementioned derivatizing reactions, thenaphthalene which is produced can be converted to other naphthalenecompounds within the scope of this invention.

The compounds of this invention are valuable pharmaceutical agents. Theyexhibit anti-fertility activity, and they especially are useful asorally active anti-fertility agents in birds and mammals. The compoundsof this invention thus are useful in controlling the animal populationand as contraceptives in living beings. The compounds of this inventionalso are valuable for animal pest control. For example, the compounds ofthis invention can be formulated in combination with baits and/orattractants and placed in feeding stations accessible to undesirablerodents and other small animals including Canidae such as coyotes,foxes, wolves, jackals, and wild dogs, and birds, such as starlings,galls, redwing blackbirds, pigeons, and the like, to greatly reduce thepopulation thereof. By reason of the activity of the compounds of thisinvention, they can be used to reduce hazards to aviation by lesseningthe presence of birds and animals on runways and in the vicinity of airfields. The compounds of this invention also can be used to reduce thepopulation of undesirable birds and animals so as to aid in theprevention and the spread of disease, and to reduce the destruction ofproperty in both rural and urban areas.

The compounds of this invention can be administered as such, or they canbe compounded and formulated into pharmaceutical preparations in unitdosage form for oral or parenteral administration. In the compounding orformulation, organic or inorganic solids and/or liquids which arepharmaceutically acceptable carriers can be employed. Suitable suchcarriers will be well recognized by those of ordinary skill in the art.The compositions may take the form of tablets, powder granules,capsules, suspensions, solutions, and the like.

The compounds of this invention, when administered in an effectiveamount, will produce the inhibition of pregnancy in mammals. The usualdaily dose is from about 0.02 milligrams to about 20 milligrams perkilogram body weight of the recipient. The preferred daily dose is fromabout 0.02 milligrams to about 0.4 milligrams per kilogram body weightof the recipient.

Examples of compounds of this invention include the following:

2-(3-hydroxybenzoyl)-3-phenylindene;

2-(2-methoxybenzoyl)-3-phenylindene;

2-(3-chlorobenzoyl)-3-phenylindene;

2-(2-bromobenzoyl)-3-phenylindene;

2-(4-isopropoxybenzoyl)-3-phenylindene;

2-(3-t-butyloxybenzoyl)-3-phenylindene;

2-(4-pentyloxybenzoyl)-3-phenylindene;

2-(3-cyclopentyloxybenzoyl)-3-phenylindene;

2-(4-cyclohexyloxybenzoyl)-3-phenylindene;

2-(3-ethoxybenzoyl)-3-phenylindene;

2-(2-hydroxybenzoyl)-3-(4-hexamethyleneiminoethoxyphenyl)indene;

2-(3-methoxybenzoyl)-3-[4-(2-dimethylaminoethoxy)phenyl]indene;

2-(2-isopropoxybenzoyl)-3-[4-(2-diethylaminoethoxy)phenyl]indene;

2-(4-t-butyloxybenzoyl)-3-[4-(2-pyrrolidinoethoxy)-phenyl]indene;

2-(3-pentyloxybenzoyl)-3-[4-(2-piperidinoethoxy) phenyl]indene;

2-(4-cyclopentyloxybenzoyl)-3-[4-(2-morpholinoethoxy)phenyl]indene;

2-(3-cyclohexyloxybenzoyl)-3-[4-(2-pyrrolidinoethoxy)phenyl]indene;

2-(4-chlorobenzoyl) -3-[4-(2-dimethylaminoethoxy) phenyl]indene;

2-(3-bromobenzoyl) -3-[4-(2-diethylaminoethoxy) phenyl]indene;

2-(4-methoxybenzoyl) -3-[4-(2-pyrrolidinoethoxy) phenyl]indene;

2-(3-hydroxybenzoyl) -3-[4-(2-piperidinoethoxy)phenyl]indene;

2-(4-hydroxybenzoyl)-3-[4- (2-morpholinoethoxy) phenyl]indene;

2-(4-hydroxybenzoyl)-3-phenyl-5-hydroxyindene;

2-(4-methoxybenzoyl)-3-phenyl-6-methoxyindene;

2-(4-isopropoxybenzoyl)-3-phenyl-5-ethoxyindene;

2-(3-t-butyloxybenzoyl)-3-phenyl-6-propoxyindene;

2-(4-pentyloxybenzoyl)-3-phenyl-6-cyclohexyloxyindene;

2-(3-cyclopentyloxybenzoyl)-3-phenyl-6-hydroxyindene;

2-(4-cyclohexyloxybenzoyl)-3-phenyl-5-ethoxyindene;

2-benzoyl-3-phenyl-6-methoxyindene;

2-benzoyl-3-phenyl-6-hydroxyindene;

2-benzoyl-3-(4-hexamethyleneiminoethoxyphenyl)-6-methoxyindene;

2-benzoyl-3-[4-(2-pyrrolidinoethoxy)phenyl]-5-hydroxyindene;

2-benzoyl-3-[4-(2-piperidinoethoxy)phenyl]-6-ethoxyindene;

2-benzoyl-3-[4-(2-morpholinoethoxy)phenyl]-6-ethoxyindene;

2-benzoyl-3-phenyl-5-cyclopentyloxyindene;

2-benzoyl-3-phenyl-6-pentyloxyindene;

2-benzoyl-3-phenyl-5-ethoxyindene;

2-benzoyl-3-phenyl-6-isopropoxyindene;

2-benzoyl-3-(4-hexamethyleneiminoethoxyphenyl)-5-butyloxyindene;

2-benzoyl-3-phenyl-5-hydroxyindene;

3-(3-hydroxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(2-methoxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(4-isopropoxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(3-t-butyloxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(4-pentyloxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(3-cyclopentyloxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(4-cyclohexyloxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(4-chlorobenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(2-bromobenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(3-ethoxybenzoyl)-4-phenyl-1,2-dihydronaphthalene;

3-(2-hydroxybenzoyl)-4-(4-hexamethyleneiminoethoxyphenyl)-1,2-dihydronaphthalene;

3-(3-methoxybenzoyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(2-isopropoxybenzoyl)-4-[4-(2-diethylaminoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(4-t-butyloxybenzoyl)-4-[4-(2-pyrrolidinoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(3-pentyloxybenzoyl)-4-[4-(2-piperidinoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(4-cyclopentyloxybenzoyl)-[4-(2-morpholinoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(3-cyclohexyloxybenzoyl)-4-[4-(2-pyrrolidinoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(4-chlorobenzoyl)-4-[4-(2-dimethylaminoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(3-bromobenzoyl)-4-[4-(2-diethylaminoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(4-methoxybenzoyl)-4-[4-(2-pyrrolidinoethoxy)phenyl]-1,2-dihydronaphthalene;

3-(3-hydroxybenzoyl)-4-[4-(2-piperidinoethoxy)-phenyl]-1,2-dihydronaphthalene;

3-(4-hydroxybenzoyl)-4-[4-(2-morpholinoethoxy)-phenyl]-1,2-dihydronaphthalene;

3-(4-hydroxybenzoyl)-4-phenyl-6-hydroxy-1,2-dihydronphthalene;

3-(4-methoxybenzoyl)-4-phenyl-7-methoxy-1,2-dihydronaphthalene;

3-(4-isopropoxybenzoyl)-4-phenyl-6-ethoxy-1,2-dihydronaphthalene;

3-(3-t-butyloxybenzoyl)-4-phenyl-7-propoxy-1,2-dihydronaphthalene;

3-(4-pentyloxybenzoyl)-4-phenyl-7-cyclohexyloxy-1,2-dihydronaphthalene;

3-(3-cyclopentyloxybenzoyl)-4-phenyl-7-hydroxy-1,2-dihydronaphthalene;

3-(4-cyclohexyloxybenzoyl)-4-phenyl-6-ethoxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-7-methoxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-7-hydroxy-1,2-dihydronaphthalene;

3-benzoyl-4-(4-hexamethyleneiminoethoxyphenyl)-7-methoxy-1,2-dihydronaphthalene;

3-benzoyl-4-[4-(2-pyrrolidinoethoxy)phenyl]-6-hydroxy-1,2-dihydronaphthalene;

3-benzoyl-4-[4-(2-piperidinoethoxy)phenyl]-7-ethoxy-1,2-dihydronaphthalene;

3-benzoyl-4-[4-(2-morpholinoethoxy)phenyl]-7-methoxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-6-cyclopentyloxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-7-pentyloxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-6-ethoxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-7-isopropoxy-1,2-dihydronaphthalene;

3-benzoyl-4-(4-hexamethyleneiminoethoxyphenyl)6-butyloxy-1,2-dihydronaphthalene;

3-benzoyl-4-phenyl-6-hydroxy-1,2-dihydronaphthalene;

1-phenyl-2-(3-hydroxybenzoyl)naphthalene;

1-phenyl-2-(4-chlorobenzoyl)naphthalene;

1-phenyl-2-(2-bromobenzoyl)naphthalene;

1-phenyl-2-(2-methoxybenzoyl)naphthalene;

1-phenyl-2-(4-isopropoxybenzoyl)naphthalene;

1-phenyl-2-(3-t-butyloxybenzoyl)naphthalene;

1-phenyl-2-(4-pentyloxybenzoyl)naphthalene;

1-phenyl-2-(3-cyclopentyloxybenzoyl)naphthalene;

1-phenyl-2-(4-cyclohexyloxybenzoyl)naphthalene;

1-phenyl-2-ethoxybenzoylnaphthalene;

1-(4-hexamethyleneiminoethoxyphenyl)-2-(2-hydroxybenzoyl)naphthalene;

1-[4-(2-dimethylaminoethoxy)phenyl]-2-(3-methoxybenzoyl)naphthalene;

1-[4-(2-diethylaminoethoxy)phenyl]-2-(2-isopropoxybenzoyl)naphthalene;

1-[4-(2-pyrrolidinoethoxy)phenyl]-2-(4-t-butyloxybenzoyl)naphthalene;

1-[4-(2-piperidinoethoxy)phenyl]-2-(3-penthloxybenzoyl)naphthalene;

1-[4-(2-morpholinoethoxy)phenyl]-2-(4-cyclopentyloxybenzoyl)naphthalene;

1-[4-(2-pyrrolidinoethoxy)phenyl]-2-(3-cyclohexyloxybenzoyl)naphthalene;

1-[4-(2-dimethylaminoethoxy)phenyl]-2-(4-chlorobenzoyl)naphthalene;

1-[4-(2-diethylaminoethoxy)phenyl]-2-(3-bromobenzoyl)naphthalene;

1-[4-(2-pyrrolidinoethoxy)phenyl]-2-(4-methoxybenzoyl)naphthalene;

1-[4-(2-piperidinoethoxy)phenyl]-2-(2-hydroxybenzoyl)naphthalene;

1-[4-(2-morpholinoethoxy)phenyl]-2-(4-hydroxybenzoyl)naphthalene;

1-phenyl-2-(4-hydroxybenzoyl)-6-hydroxynaphthalene;

1-phenyl-2-(4-methoxybenzoyl)-7-methoxynaphthalene;

1-phenyl-2-(4-isopropoxybenzoyl)-6-ethoxynaphthalene;

1-phenyl-2-(3-t-butyloxybenzoyl)-7-propoxynaphthalene;

1-phenyl-2-(4-pentyloxybenzoyl)-7-cyclohexyloxynaphthalene;

1-phenyl-2-(3-cyclopentyloxybenzoyl)-7-hydroxynaphthalene;

1-phenyl-2-(4-cyclohexyloxybenzoyl)-6-ethoxynaphthalene;

1-phenyl-2-benzoyl-7-methoxynaphthalene;

1-phenyl-2-benzoyl-7-hydroxynaphthalene;

1-(4-hexamethyleneiminoethoxyphenyl)-2-benzoyl-7-methoxynaphthalene;

1-[4-(2-pyrrolidinoethoxy)phenyl]-2-benzoyl-6-hydroxynaphthalene;

1-[4-(2-piperidinoethoxy)phenyl]-2-benzoyl-7-ethoxynaphthalene;

1-[4-(2-morpholinoethoxy)phenyl]-2-benzoyl-7-methoxynaphthalene;

1-phenyl-2-benzoyl-6-cyclopentyloxynaphthalene;

1-phenyl-2-benzoyl-7-pentyloxynaphthalene;

1-phenyl-2-benzoyl-6-ethoxynaphthalene;

1-phenyl-2-benzoyl-7-isopropoxynaphthalene;

1-(4-hexamethyleneiminoethoxyphenyl)-2-benzoyl-6-butyloxynaphthalene;

1-phenyl-2-benzoyl-6-hydroxynaphthalene; and the like.

The following examples are illustrative of the preparation andactivities of the compounds of this invention. They are not intended tobe limiting upon the broad scope thereof.

EXAMPLE 1 Preparation of 2-(4-Methoxybenzoyl)-3-phenyl-6-methoxyindene.

A mixture of 5 gms. of β-(3-methoxyphenyl)-propionic acid inpolyphosphoric acid was prepared. The mixture was heated for 2 hours at120° C. The mixture then was cooled, and ice was added. The resultingsolid was removed by filtration and dissolved in benzene. The benzenesolution was filtered and concentrated to one-fourth volume. Petroleumether was added and the mixture was cooled to 5° C. The product,1-oxo-5-methoxyindane was collected by filtration, m.p. 105°-107° C.

Anaylsis, Calcd. for C₁₀ H₁₀ O₂ : C, 74.06; H, 6.22; O, 19.73. Found: C,74.32, H, 6.42; O, 20.03.

A solution of 22.2 gms. (0.137 mole) of the oxoindane in tetrahydrofuran(THF) was added dropwise to a cold suspension of 11 gms. (0.274 mole) ofsodium amide in THF. The resulting mixture was stirred for 10 minutes,and a solution of 31.3 gms. (0.137 mole) of phenyl p-methoxybenzoate inTHF was added. Cooling was discontinued, and a slight exothermicreaction occurred. The mixture was stirred at room temperature for 2hours. A thick precipitate developed, and the reaction mixture waspoured into ice-water. The aqueous mixture then was extracted with ethylacetate to obtain 20.7 gms. of1-oxo-2-(4-methoxybenzoyl)-5-methoxyindane, m.p. 160°-162° C.

A slurry of 20.5 gms. (0.0694 mole) of the diketone prepared above inbenzene was added as a slow stream to solution of a five-fold excess ofphenyl magnesium bromide in ether. The resulting mixture then wasrefluxed for 4 hours. The mixture was cooled and poured into a mixtureof ice and sulfuric acid. The mixture then was extracted with ethylacetate, washed with water and then with aqueous sodium bicarbonate, anddried over magnesium sulfate. The mixture then was concentrated to 28gms. of a dark red oil. A mixture of 20 percent ether in methanol (25ml.) was added. Part of the oil crystallized on standing at roomtemperature and was isolated by filtration to obtain 7.5 gms. ofred-brick crystals. This material was slurried in a hot mixture ofbenzene and acetone. The insoluble solid was separated by filtration.The filtrate was concentrated to dryness, and the residue wasrecrystallized from ether to obtain 5.4 gms. of the product, m.p.113°-114° C.

The filtrate from the aforementioned separation of the red-brickcrystals was concentrated and chromatographed on silica with benzene aseluant. From this chromatographic separation were obtained an additional3 gms. of the title compound, m.p. 113°-114° C.

These two portions of product were combined, recrystallized fromacetone, and air dried to obtain the title compound, m.p. 115°-116° C.

Analysis, Calcd. for C₂₄ H₂₀ O_(3:) C, 80.88; H, 5.66; O, 13.47. Found:C, 80.95; H, 5.84; O, 14.42.

EXAMPLE 2 PREPARATION OF 2-(4-METHOXYBENZOYL)-3-PHENYLINDENE.

A slurry of 13.25 gms. (0.05 mole) of 1-oxy-2-(4-methoxybenzoyl)indane(prepared by a sequence analoqous to that described in Example 1) in amixture of 300 ml. of ether and 200 ml. of benzene was prepared. To theslurry were added 35.657 gms. (0.197 mole) of phenylmagnesium bromide.The resulting mixture was refluxed overnight. The mixture then waspoured into a mixture of ice and sulfuric acid, and the resultingorganic layer was separated, washed with aqueous sodium bicarbonatesolution, and dried over sodium sulfate. The organic solution then wasconcentrated to a red residue. The residue was dissolved in a smallamount of ether and cooled. White-pink crystals (2.0 gms.) formed andwere collected by filtration, m.p. 200°-202° C.

The filtrate was concentrated to dryness, and the residue crystallizedon standing. Methanol was added to the residue, and the mixture wasfiltered to abtain 9.3 gms. of the title compound, m.p. 114°-115° C.

Analysis, Calcd. for C₂₃ H₁₈ O₂ : C, 84.64; H, 5.56; O, 9.80. Found: C,84.69; H, 5.82; O, 9.79.

EXAMPLE 3 PREPARATION OF 2-(4-HYDROXYBENZOYL)-3-PHENYL-6-HYDROXYINDENE.

To a solution of 4 gms. of the product from Example 1 in dichloromethanewere added two equivalents of boron tribromide. The resulting mixturewas stirred for 24 hours. Analysis of the reaction mixture by TLCindicated the presence of starting material, product, and some of themonohydroxy compound. Another equivalent of boron tribromide was added,and the mixture was stirred for a total of 72 hrs. TLC indicated nostarting material and only traces of the monohydroxy derivative. Theproduct was chromatographed on silica using a mixture of 10 percentethyl acetate and 90 percent benzene to obtain 3 gms. of the titlecompound, m.p. 191°-192° C.

Analysis, Calcd. for C₂₂ H₁₆ O₃ : C, 80.47; H, 4.91; O, 14.62. Found: C,80.28; H, 4.98; O, 14.71.

EXAMPLE 4 PREPARATION OF3-(4-METHOXYBENZOYL)-4-PHENYL-7-METHOXY-1,2-DIHYDRONAPHTHALENE.

To a suspension of 10.5 gms. of sodium amide in THF were added 23.2 gms.of 6-methoxy-α-tetralone in THF. The resulting mixture was stirred for10 minutes, and a solution of 30 gms. of phenyl p-methoxybenzoate in THFwas added. The resulting mixture was stirred at room temperatureovernight. The THF then was concentrated in vacuo. Water was added tothe residue. The solid that did not dissolve in the water was removed byfiltration and slurried in hot methanol. The methanol was cooled to roomtemperature and filtered to give 24.3 gms. of2-(4-methoxybenzoyl)-6-methoxy-α-tetralone, m.p. 112°-113° C.

Analysis, Calcd. For C₁₉ H₁₈ O₄ : C, 73.53; H, 5.85; O, 20.62 Found: C,72.23; H, 6.55; O, 2.67

Mass spectrum: Theory, 310; Found, 310.

To 500 ml. of a 1:1 mixture of ether and benzene were added 21.7 gms.(0.07 mole) of the above-prepared tetralone. The resulting slurry wasadded to 146 ml. of a 2.05 molar solution of phenylmagnesium bromide inether (represents 0.3 moles of phenylmagnesium bromide). The resultingmixture turned green and was refluxed for 4 hours. The mixture then waspoured into a mixture of ice and sulfuric acid. The resulting mixturethen was extracted with ethyl acetate. The ethyl acetate extract waswashed successively with water, aqueous sodium bicarbonate, and water,and then was dried over magnesium sulfate. The ethyl acetate solutionwas concentrated to dryness, and the residue, a red-yellow oil, wascrystallized from ether to obtain 13.8 gms. of the title compound aswhite crystals, m.p. 107°-108° C. Analysis, Calcd. for C₂₅ H₂₂ O₃ : C,81.06; H, 5.99; O, 12.96. Found: C, 81.14; H, 5.79; O, 12.93.

Mass spectrum: Theory, 370; Found, 370; 339

EXAMPLE 5 Preparation of3-(4-Hydroxybenzoyl)-4-phenyl-7-hydroxy-1,2-dihydronaphthalene.

To 300 ml. of DMF were added under nitrogen and with ice bath cooling,9.3 gms. of ethyl mercaptan. To the mixture then were added 7.2 gms. ofa 50 percent sodium hydride-oil mixture. The mixture represents 0.15mole of sodium hydride. To the resulting mixture then were added 11.1gms. (0.03 mole) of the product from Example 1. The mixture was heatedat 60° C. for 1 hour. Analysis of the reaction mixture by TLC indicatedthe presence of starting material plus another component, probably themono-hydroxy compound. The temperature of the reaction mixture wasraised to 110° C., and this temperature was maintained for one hour. TLCshowed no starting material; however, the presence of two components wasnoted. The reaction mixture therefore was heated for an additional onehour at 125° C. after which a single spot was noted by TLC analysis. Thereaction mixture then was acidified by addition of cold 1N hydrochloricacid. The mixture was extracted with ethyl acetate. The ethyl acetatewas washed with water and evaporated. The resulting residue wasrecrystallized from a mixture of methanol and acetone to give 8 g. ofthe title compound, m.p. 205°-207° C.

Analysis, Calcd. for C₂₃ H₁₈ O₃ : C, 80,68; H, 5.30; O, 14.02. Found: C,80.38; H, 5.43; O, 14.28.

EXAMPLE 6 Preparation of1-Phenyl-2-(4-methoxybenzoyl)-6-methoxynaphthalene.

To 11.1 g. (0.03 mole) of the product from Example 4 dissolved inbenzene were added 9.0 g. of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone(DDQ). The mixture was refluxed for two hours and then was filteredwhile hot through silica, and the silica was washed three times withethyl acetate. The ethyl acetate washings were combined with the benzenereaction mixture, and the total was concentrated to dryness. The residuewas dissolved in hot methanol, and the solution was allowed to cool toobtain 4.5 g. of product. The product was recrystallized again frommethanol to obtain the title compound, m.p. 122°-124° C.

Analysis, Calcd. for C₂₅ H₂₀ O₃ : C, 81.50; H, 5.47; O, 13.03. Found: C,81.52; H, 5.68; O, 12.93.

Mass spectrum; Theory, 368; Found, 368.

The compounds of this invention are tested for anti-fertility activityin accordance with the following procedure:

Fifty young adult virgin female rats weighing 200-230 g. each areseparated into ten groups of five each. One of the groups serves as thecontrol group and the other nine groups as experimental groups, eachsuch experimental group receiving test compound at a particular doselevel. The test compound for each group of five rats is prepared in cornoil such that the daily administration is in 0.1 ml. of vehicle. Thedesignated quantity of the test compound in the vehicle is administeredto each rat within the defined group subcutaneously (sc) daily. Thecontrol group receives only the vehicle. Administration of the vehicleor the combination of test compound and vehicle is continued on a dailybasis for 15 days. On the 5th day of treatment, two adult male ratsweighing at least 250 g. each are added to each group, and cohabitationis continued until the 15th day at which time the male rats arewithdrawn from the group. Each group of female rats then is maintainedfor an additional 7 days after which the rats are sacrificed andexamined for the presence of viable or resorbing fetuses.

The number of animals that exhibit evidence of pregnancy over the numberof animals in the group is the pregnancy ratio. A compound is consideredactive when the ratio is 0/5 or 1/5. A ratio of 2/5 consitutes marginalactivity, and anything higher is inactive.

The Table following illustrates the antifertility activity of compoundsof this invention.

                                      Table                                       __________________________________________________________________________    Antifertility Activity                                                         ##STR15##                                                                    Compound                  dose   Pregnancy Ratio                              R R.sub.1                                                                             R.sub.2                                                                             R.sub.3                                                                          X        mg./day                                                                              P/5 P =                                      __________________________________________________________________________    H H     4-OCH.sub.3                                                                         H  CH.sub.2 1.0     0.sup.a                                                               0.1    0                                                                      0.05   4                                            H OCH.sub.3                                                                           4-OCH.sub.3                                                                         H  CH.sub.2 5.0    0                                                                      1.0    0                                                                      0.5     0.sup.a                                                               0.1     0.sup.b                                                               0.5    0                                                                      0.01   4                                                                      0.005  4                                            H OCH.sub.3                                                                           4-OCH.sub.3                                                                         H  CH.sub.2CH.sub.2                                                                       1.0    0                                                                      0.5    0                                                                      0.1    1                                                                      0.05   3                                            H OH    4-OH  H  CH.sub.2 0.5    0                                                                      0.05   0                                                                      0.01   0                                                                      0.005  0                                                                      0.001  4                                                                      0.0005 4                                            H OH    4-OH  H  CH.sub.2CH.sub.2                                                                       0.5     0.sup.a                                                               0.1    0                                                                      0.05   0                                                                      0.01   4                                                                      0.005  5                                            H OCH.sub.3                                                                           4-OCH.sub.3                                                                         H  CHCH     5.0    2                                                                      1.0    3                                            __________________________________________________________________________     .sup.a Pregnancy ratio is 0/4.                                                .sup. b Pregnancy ratio is 0/3.                                          

We claim:
 1. A compound of the formula ##STR16## in which X is --CH₂ --,--CH₂ -CH₂ -- or --CH═CH--; R and R₁ independently are hydrogen,hydroxyl, C₁ - to C₅ -alkoxy, or C₅ - to C₆ -cycloalkoxy; subject to thelimitation that at least one of R and R₁ is hydrogen; R₂ is hydrogen,chloro, bromo, hydroxyl, C₁ - to C₅ -alkoxy, or C₅ - to C₆ -cycloalkoxy;subject to the limitation that at least one of R, R₁, or R₂ is otherthan hydrogen; and R₄ and R₅ independently are C₁ -C₄ alkyl, or R₄ andR₅ taken together with the nitrogen to which they are bonded constitutea heterocyclic ring selected from the group consisting of pyrrolidino,piperidino, hexamethyleneimino, or morpholino; and pharmaceuticallyacceptable non-toxic acid addition salts thereof.
 2. Compound of claim1, in which X is --CH₂ -CH₂ --.
 3. Compound of claim 2, in which R₁ ishydroxyl.
 4. Compound of claim 2, in which R₂ is hydroxyl.
 5. Compoundof claim 4, in which the R₂ substituent is in the para position. 6.Compound of claim 5, in which R₁ is hydroxyl.
 7. Compound of claim 2, inwhich R₄ and R₅ are methyl.
 8. Compound of claim 2, in which R₄ and R₅are ethyl.
 9. Compound of claim 2, in which R₄ and R₅ taken togetherwith the nitrogen to which they are bonded constitute a pyrrolidinofunction.
 10. Compound of claim 2, in the form of its pharmaceuticallyacceptable non-toxic salt.
 11. Compound of claim 10, in the form of itscitrate salt.
 12. Compound of claim 1, in which X is --CH₂ --. 13.Compound of claim 12, in which R₁ is hydroxyl.
 14. Compound of claim 12,in which R₂ is hydroxyl.
 15. Compound of claim 14, in which the R₂substituent is in the para position.
 16. Compound of claim 15, in whichR₁ is hydroxyl.
 17. Compound of claim 15, in which R₁ is methoxy. 18.Compound of claim 1, in which X is --CH═CH--.